PROMISE

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Douglas PS, et al. "Outcomes of anatomical versus functional testing for coronary artery disease". The New England Journal of Medicine. 2015. 372(14):1291-1300.
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Clinical Question

In patients with new stable angina, does evaluation with coronary computed tomographic angiography (CCTA) result in improved outcomes compared with evaluation using functional testing?

Bottom Line

Evaluation of new stable angina with CCTA compared to functional testing did not result in improvement in the composite outcome of death from any cause, nonfatal myocardial infarction, hospitalization for unstable angina, or major procedural complications.

Major Points

Anatomical testing with Coronary CT angiography to detect coronary artery disease is a promising tool in evaluating stable angina, with the potential to identify prognostically significant lesions that would be missed by functional testing (nuclear stress testing, stress echocardiography, or exercise ECG). Unfortunately, this trial did not show an improvement in the primary composite outcome of death from any cause, nonfatal myocardial infarction, hospitalization for unstable angina, or major procedural complication after a median of 25 months of follow-up. The primary endpoint also did not meet the prespecified noninferiority margin of 1.10. The authors note that the event rate of 3.1% was lower than expected, presumably due to high rates of appropriate medical therapy in both groups, which may have decreased the study's ability to detect a difference between groups if present.

This study is in contrast to the more recent SCOT-HEART study 5-year results [1], which found a decrease in the composite end point of death from CHD or nonfatal myocardial infarction in the CCTA group compared to standard of care, driven by nonfatal myocardial infarction. Unlike the PROMISE study, the patients in the CCTA group of SCOT-HEART were more likely to have started preventative therapies compared to standard of care. As noted in the accompanying editorial, it is unknown whether either functional testing or anatomical testing improves outcomes compared to medical therapy alone in these patients, as neither study was designed to address that question. [2]

Guidelines

The 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guidelines were written before the results of this trial were published.[3]

  • Class IIB recommendation: "CCTA might be reasonable for patients with an intermediate probability of IHD who have at least moderate physical functioning or no disabling comorbidity" in patients able to exercise.
  • Class IIA recommendation: CCTA is reasonable for patients with low to intermediate pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity" in patients unable to exercise."
  • Class IIA recommendation: "CCTA is reasonable for patients with an intermediate pretest probability of IHD who a) have continued symptoms with prior normal test findings, or b) have inconclusive results from prior exercise or pharmacological stress testing, or c) are unable to undergo stress with nuclear MPI or echocardiography."

The 2013 ESC guidelines were also written before the results of this trial were published. [4]

Design

  • Multicenter, randomized, controlled trial
  • N=10,003
    • CCTA (n=4996)
    • Functional testing (n=5007)
  • Setting: 193 cardiology, radiology, primary care, urgent care, and anesthesiology sites in Canada and the United States
  • Enrollment: July 27, 2010 to September 19, 2013
  • Median follow-up: 25 months (interquartile range: 18-34 months)
  • Analysis: Intention-to-treat
  • Primary outcome: composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis, and renal failure), or hospitalization for unstable angina.

Population

Inclusion Criteria

  • New or worsening chest pain or equivalent symptoms suspicious for coronary artery disease
  • No prior cardiac evaluation for this episode of symptoms
  • Planned noninvasive testing for diagnosis
  • Men age >/= 55 years and women age >/= 65 years of age
  • If age 45 to 54 man or 50 to 64 woman, then must have >/= 1 of following risk factors:
    • diabetes mellitus requiring medical treatment
    • peripheral arterial disease, defined as documented peripheral arterial stenosis >/= 50%, treated medically or invasively
    • cerebrovascular disease, defined as documented carotid stenosis >/= 50%, treated medically or invasively
    • ongoing tobacco use
    • hypertension
    • abnormal ankle-brachial index, defined as <0.9
    • dyslipidemia
  • Serum creatinine </= 1.5 mg/dL within the past 90 days
  • Negative urine/serum pregnancy test result for female subjects of childbearing potential

Exclusion Criteria

  • Diagnosed or suspected acute coronary syndrome requiring hospitalization or urgent or emergent testing; elevated troponin or CK-MB
    • outpatients who have completed a rule-out ACS protocol were still eligible if they had 2 sets of negative biomarkers and a non diagnostic or normal EKG
  • Hemodynamically or clinically unstable condition (systolic BP < 90 mm Hg, severe atrial or ventricular arrhythmias, or persistent resting chest pain felt to be ischemic despite adequate therapy)
  • Known coronary artery disease with clinical history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, or any angiographic evidence of coronary artery disease >/= 50% lesion in a major epicardial vessel
  • Any invasive coronary angiography or noninvasive anatomical or functional cardiovascular test for detection of coronary artery disease within previous 12 months (+/- 30 days)
  • Known significant congenital, valvular (moderate or greater), or cardiomyopathy process (hypertrophic cardiomyopathy or LV ejection fraction < 40%) that could explain cardiac symptoms.
  • Contraindication to CCTA, including allergy to contrast or pregnancy
  • Any other contraindications that would preclude performing a CCTA per local site practice, such as >/= 1 of the following:
    • Inability to receive beta-blockers if heart rate is > 65 beats/min
    • Agatston score > 800
    • BMI > 40 kg/m^2
    • Cardiac arrhythmia
  • Life expectancy < 2 years
  • Unable to provide written informed consent or participate in long-term follow-up

Baseline Characteristics

  • Mean age: 60.8
  • Sex: 52.7% women
  • Belong to racial or ethnic minority group: 22.6%
  • Cardiovascular Risk Factors:
    • Diabetes: 21.4%
    • Hypertension: 65.0%
    • Past or current tobacco users: 51.1%
    • Dyslipidemia: 67.7%
    • Family history of premature CAD: 32.1%
  • Mean number of the above five risk factors: 2.4
  • 2.6% enrolled by meeting the age criteria alone
  • Mean pretest likelihood of obstructive disease according to combined Diamond and Forrester and Coronary Artery Surgery Study: 53.3 +/- 21.4%

Interventions

  • Randomized to CCTA or functional-testing group
    • Stratified according to study site and choice of intended functional test prior to randomization
  • All subsequent decisions were made by local physician performing and interpreting tests
  • Follow-up visits at 60 days at study sites and centrally by telephone or mail every 6 months from randomization for a minimum of 1 year

Outcomes

Comparisons are CCTA vs. functional testing.

Primary Outcomes

Composite of Death from any cause, nonfatal myocardial infarction, hospitalization for unstable angina, major procedural complication
164 vs. 151 (HR 1.04; 95% CI 0.83-1.29; P=0.75)

Secondary Outcomes

Primary endpoint plus catheterization showing no obstructive CAD
332 vs. 353 (HR 0.91; 95% CI 0.78-1.06; P=0.22)
Death or nonfatal myocardial infarction
104 vs. 112 (HR 0.88; 95% CI 0.67-1.15; P=0.35)
Death, nonfatal myocardial infarction, or hospitalization for unstable angina
162 vs. 148 (HR 1.04; 95% CI 0.84-1.31; P=0.70)

Adverse Events

Invasive catheterization showing no obstructive CAD
3.4% vs 4.3% (P=0.02)
Cumulative radiation exposure in all procedures </= 90 days after randomization (in mSv)
12.0+/-8.5 vs 10.1+/-9.0 (P<0.001)

Criticisms

  • There were fewer events than expected, which may have underpowered the study to detect a difference between the groups if present.

Funding

National Heart, Lung, and Blood Institute at the NIH

Further Reading

  1. Newby DE et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. N. Engl. J. Med. 2018. 379:924-933.
  2. Kramer CM & Cardiovascular imaging and outcomes--PROMISEs to keep. N. Engl. J. Med. 2015. 372:1366-7.
  3. Fihn SD et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012. 126:e354-471.
  4. Montalescot G et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 2013. 34:2949-3003.